The lung is an organ that is dependent on delicate structures such as the alveolar-capillary interface for its crucial gas-exchange function, yet is routinely exposed to toxins and irritants in the inspired air. It can also be injured by toxins and inflammatory products generated by infections and derangements elsewhere in the body. It is thus subject to a wide variety of diseases, for many of which the pathogenesis is incompletely known. Some of these diseases and conditions have effective treatments available; these treatments may include administration of steroids, other anti-inflammatory agents, small molecules, or therapeutic antibodies. However, for some diseases and conditions and subsets of patients with other conditions, efficacy of all available treatments is limited. The most commonly employed treatment in many cases is corticosteroid administration, which is often associated with significant adverse effects.
Pulmonary fibrosis is a lung disease that can result from exposure to radiation, from infections, from inflammatory processes, or from autoimmune disorders. In other cases, known as idiopathic pulmonary fibrosis (IPF), the cause is unknown. Regardless of the triggering insult, the outcome is uncontrollable inflammation, immune activity, lung injury/repair, and fibrotic processes that damage the lung. The scarring of the lungs that occurs in these diseases reduces the ability of the lungs to transfer oxygen into the blood, causing hypoxemia. A primary aim of a treatment for pulmonary fibrosis is to reduce inflammation and injury and enhance lung repair, and thus to halt the abnormal processes that result in irreversible fibrosis. Currently available therapies for pulmonary fibrosis are very limited.
Chronic obstructive pulmonary disease (COPD) is a growing problem. Patients present with symptoms of cough, excessive production of mucus, and dyspnea that may be connected with bronchitis or emphysema. While bronchitis represents inflammation of the airways, emphysema is a more advanced disease representing destruction of the lung parenchyma by oxidants and proteases released as part of the inflammatory process. Development of COPD is most often attributed to smoking or exposure to environmental toxins over a period of many years, although the disease continues to progress even after smoking cessation. The pathophysiology in COPD also features “steroid resistance,” mediated by reduced HDAC (histone deacetylase) enzyme activity. As a result, the most commonly used anti-inflammatory drug has little effect and is incapable of halting progression. The only treatment available for COPD is administration of drugs that alleviate the symptoms.
A pulmonary disease with symptoms often overlapping those of COPD is asthma. Airway inflammation in asthma is characterized by activation of a variety of immune-system cells. Asthma pathology features increased production of a number of cytokines, primarily of the Th2 class associated with adaptive immunity, together with tissue eosinophilia and increased IgE production. A diagnostic feature of asthma is excessive response of the airways to bronchoconstrictors such as methacholine. The most effective therapy for asthma remains corticosteroids, typically administered by inhalation. Bronchodilators are also employed, frequently in combination with corticosteroids. Some patients, however, exhibit “steroid resistant” asthma that does not respond to corticosteroids.
Cystic fibrosis is a genetic disease affecting a chloride ion channel in the membrane of epithelial cells. Failure of chloride ion transport results in production of thick, viscous secretions. Mucus production in the lungs is among the many secretions affected. A prominent feature of cystic fibrosis is inflammation that is only partially due to the frequent infections that are also a feature of the disease. This neutrophil-rich inflammation is one factor in the gradual loss of lung function that eventually leads to death. Therapies involved in attenuating lung function decline are limited.
ALI (acute lung injury) and ARDS (acute respiratory distress syndrome) are lung diseases that can result from a wide variety of injuries either intrinsic or extrinsic to the lung. In the acute phase there is sloughing of both bronchial and alveolar epithelial cells, with formation of protein-rich hyaline membranes on the denuded basement membrane. This leads to inflammation, with neutrophils adhering to the injured capillary endothelium and migrating through the interstitium into the air space. In the air space, alveolar macrophages secrete pro-inflammatory cytokines, which act locally to stimulate chemotaxis and activate neutrophils that release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor. The oxidants and proteases produce more injury, and the cycle continues. There is no approved pharmacological therapy for ALI/ARDS.
Ischemia-reperfusion injury occurs when blood flow returns to an organ that has been starved of oxygen. Ischemia followed by reperfusion is inevitable in organ transplantation but also accompanies such conditions as myocardial infarction and stroke. The mechanisms involved are complex but involvement of inflammation and associated production of reactive oxygen species is common Reactive oxygen species are strong oxidants that can damage components of many cells. Organs can only withstand a limited period of ischemia before suffering injury on reperfusion. Attempts to extend this period by treatments prior to transplantation have had limited success and post-transplantation treatments appear even less useful. The most effective current method for extending the permissible period of ischemia is by reducing the organ's metabolic rate during the period between harvest and reimplantation.
Pulmonary hypertension is defined as abnormally high blood pressure specifically in the vasculature of the lungs. It is usually secondary to conditions that limit pulmonary blood flow or oxygenation but may also occur without identifiable cause. A key feature of the pathogenesis is abnormal proliferation of vascular cells together with failure of appropriate apoptosis. Current management focuses on vasodilators and symptom-reducing strategies, but compounds that block cell proliferation and other pathways are now being investigated.
Lung cancer is the leading cause of cancer death in the US, with only 16% of patients diagnosed with lung cancer surviving as much as five years. It is estimated that 80%-90% of all lung cancers are the result of cigarette smoke. Like other environmental carcinogens, which may also induce lung cancer, the carcinogens in cigarette smoke cause mutations that lead to uncontrolled proliferation of the affected cells and also allow them to invade normal tissues. Treatments are surgery, radiation, and chemotherapy, with the choice depending to some extent on the specific type of cancer involved, but only surgical removal of a tumor that has not yet spread provides any hope for long-term survival. As the poor long-term survival statistics indicate, better treatments are needed.